1. Field of the Invention
The present invention relates to diagnostic agents for pancreatic exocrine function and novel compounds.
2. Background of the Invention
“Pancreatic exocrine function tests” are useful for the diagnosis of pancreatic diseases such as chronic and acute pancreatitis and pancreatic cancer. It is also useful to assess the condition and the prognosis of patients and to control the medication of protease preparations: The general descriptions are found in Arvanitakis and Cooke, Gastroenterology, 74:932 (1978); Niederau and Grendell, Gastroenterology, 88:1973 (1985); Goldberg, Bull. Mol. Biol. Med., 15:1 (1990); Lankisch, Int. J. Pancreatology, 14:9 (1993); Bank and Chow, Gastroenterologist, 2:224 (1994); and Steer et al., New Eng. J. Med., 332:1482 (1995).
The pancreatic exocrine function tests are roughly classified into intubation tests and tubeless tests. The intubation tests involve intubating a tube through the mouth to the duodenum to collect the duodenal juice. The secretin test is commonly used wherein secretin is intravenously administered to stimulate secretion of the pancreatic juice prior to the collection. This method is highly accurate since the amounts and components of the pancreatic juice are directly analyzed and is the “gold standard” of pancreatic exocrine function test. However, this method can not be used repeatedly or used for screening because of the very strong stress caused on the patients. It is not available at only a relatively small number of medical centers since the physician must be highly skilled. Further, since this method requires fluoroscopic tube placement during the collection of the duodenal juice, there is the problem of X ray exposure.
On the other hand, tubeless tests are easy to perform for estimating the pancreatic exocrine function which requires no intubation, wherein the excreted amount of compounds produced by pancreatic exocrine enzymes or the excreted amount of the pancreatic exocrine enzymes per se are measured. At present, the following four methods are mainly used:
1. PFD test wherein a synthetic substrate BT-PABA (N-benzoyl-L-tyrosyl-p-aminobenzoic acid) for chymotrypsin secreted from the pancreas is orally administered and the amount of PABA (p-aminobenzoic acid), a product degradated by chymotrypsin, excreted into the urine is measured;2. PLT test wherein a synthetic substrate FDL (fluorescein dilaurate) for cholesterol ester hydrolase, esterase, secreted from the pancreas is orally administered and the amount of the degradation product fluorescein excreted into the urine or the concentration thereof in the blood is measured;3. Fecal chymotrypsin test wherein chymotrypsin in the feces is quantitatively determined; and4. Fecal elastase test wherein elastase in the feces is quantitatively determined.
However, the sensitivity any of these tests is too low to detect slight decreases of pancreatic exocrine function. Therefore, they have not been used that often in recent years.
To solve this problem, many easier pancreatic exocrine function tests have been searched for; 13C-breath tests have also been applied wherein a 13C-labeled compound is administered and an increase of the concentration of 13CO2 in the exhalation is measured. Examples of such 13C-breath tests are illustrated below:
1. 13C-breath test wherein a 13C-labeled lipid or mixed triglyceride, which is a substrate for lipase, is administered: Chen et al., J. Nuclear Med., 15:1125 (1974); Watkins et al., J. Lab. Clin. Med., 90:422 (1977); Ghoos et al., Digestion, 22:239 (1981); John, S G., Gastroenterology, 83:44 (1982); Watkins et al., Gastroenterology, 82:911 (1982); Benini et al., Digestion, 29:91 (1984); Jones et al., J. Lab. Clin. Med., 105:647 (1985); Knoblach et al., Monatsschr Kinderheilkd, 136:26 (1988); Vantrappen et al., Gastroenterology, 96:1126 (1989); Murphy et al., Arch. Disease in Childhood, 65:574 (1990); Kato et al., Am. J. Gastroenterol., 88:64 (1993); McClean et al., Arch. Disease in Childhood, 69:366 (1993); Jakobs et al., Eur. J. Pediatr., 156:S78 (1997); and Kalivianakis et al., Eur. J. Clin. Invest., 27:434 (1997);2. 13C-breath test wherein a 13C-labeled cholesterol ester, which is a substrate for cholesterol esterase, a lipase, is administered: Mundlos, et al., Pediatric Res., 22:257 (1987); Cole et al., Gastroenterology, 93:1372 (1987); and Mundlos et al., Gut, 31:1324 (1990);3. 13C-breath test wherein a 13C-labeled starch, which is a substrate for an amylase, is administered: Hiele et al., Gastroenterology, 96:503 (1989); Dewit et al., Pediatric Res., 32:45 (1992); and Z. Gastroenterol., 35:187 (1997); and4. 13C-breath test wherein a 13C-enriched egg protein, which is a protein having a 13C-concentration increased up to 1.4 atom % from the natural abundance of 1.1 atom % by feeding a chicken with 13C-leucine, and which is a substrate for a protease, is administered: Y. Ghoos, 13CO2-Breath Tests at the laboratory “Digestion-Absorption”, University Hospital Gasthuisberg, Leuven, Belgium (1996).
However, all these methods are less sensitive than the conventional ones and time-consuming. Therefore, these methods have not been established in clinical fields.
Thus, it is desirable that a highly sensitive pancreatic exocrine function test be developed that imparts low stress on the subject and give accurate results soon.